3-(heteroaryl-oxy)-2-alkyl-1-aza-bicycloalkyl derivatives as alpha. 7-nachr ligands for the treatment of cns diseases

ABSTRACT

The present invention relates to 1-aza-bicycloalkyl derivatives of formula (I) wherein the substituents are as defined in the specification, to processes for their production, their use as pharmaceuticals in the prevention and treatment of psychotic and neurodegenerative disorders. The claimed compounds act as nicotinic acetylcholine receptors (NACHR) ligands.

The present invention relates to novel 1-aza-bicycloalkyl derivatives,to processes for their production, their use as pharmaceuticals and topharmaceutical compositions comprising them.

More particularly the present invention provides in a first aspect, acompound of formula I

wherein

-   A and B, independently of each other, represent hydrogen or    C₁-C₇alkyl under the proviso that not both A and B can represent    hydrogen at the same time, or-   A and B together with the carbon atom to which they are attached    form a C₃-C₇cycloalkyl group; and-   X represents CH₂ or a single bond;-   Y represents a group of formula

-   -   wherein the left bond is attached to the oxygen and the right        bond is attached to the R group;

-   R represents a substituted or unsubstituted C₅-C₁₀aryl; a    substituted or unsubstituted C₅-C₁₀heteroaryl, a group N(R¹)(R⁵), or    a group N(R²)(CHR³R⁴);

-   R¹ represents hydrogen, C₁-C₄alkyl, or CF₃;

-   R² represents hydrogen, C₁-C₄alkyl, or CF₃;

-   R³ represents hydrogen, C₁-C₄alkyl, or CF₃;

-   R⁴ represents a substituted or unsubstituted C₅-C₁₀aryl or a    substituted or unsubstituted C₅-C₁₀heteroaryl;

-   R⁵ represents a substituted or unsubstituted C₅-C₁₀aryl or a    substituted or unsubstituted C₅-C₁₀heteroaryl;    in free base or acid addition salt form.

The general terms used hereinbefore and hereinafter preferably havewithin the context of this disclosure the following meanings, unlessotherwise indicated:

The term “unsubstituted or substituted” as used herein means that therespective radical can by substituted by one or more, preferably up tothree, especially one or two substituents. The substituents arepreferably selected from the group consisting of amino, C₁-C₄alkylamino, di(C₁-C₄alky)-amino, C₃-C₅cycloalkyl amino, di(C₃-C₅)cycloalkylamino, N—C₁-C₄alkyl-N—C₃-C₅cycloalkyl amino, halogen, C₁-C₄alkyl,C₄-C₆cycloalkyl, hydroxy, C₁-C₄alkoxy, C₃-C₅Cycloalkyloxy, C₁-C₄alkoxyC₁-C₄alkoxy, di(C₁-C₄alkyl)-amino C₁-C₄alkoxy, carbamoyl,N—C₁-C₄alkyl-carbamoyl, N,N-di(C₁-C₄alkyl)-carbamoyl, nitro, cyano,carboxy, C₁-C₄alkoxy carbonyl, C₁-C₄alkanoyl, C₁-C₄alkanoyloxy, benzoyl,amidino, guanidino, ureido, mercapto, C₁-C₄alkylthio, pyridyl, phenyl,phenoxy, C₁-C₄alkoxy phenyl, phenylthio, phenyl-C₁-C₄alkylthio,C₁-C₄alkylsulfonyl, phenylsulfonyl, C₁-C₄alkylphenylsulfonyl,C₁-C₄alkenyl, C₁-C₄alkanoyl, C₁-C₄alkylene dioxy bound at adjacentC-atoms of the ring, and C₁-C₄alkyl, which is substituted by halogen,hydroxy, C₁-C₄alkoxy, nitro, cyano, carboxy, C₁-C₄alkoxy carbonyl,C₁-C₄alkanoyl or C₁-C₄alkanoyloxy.

The terms “C₅-C₁₀aryl”, “C₅-C₁₀heteroaryl” are to be understood asaromatic residues which are in each case unsubstituted or substituted bythe substituents provided above, preferably in each case unsubstitutedor substituted by one or more substituents selected from halogen, CN oralkyl, which can be unsubstituted or substituted by halogen, e.g.trifluoromethyl; or C₁-C₄alkoxy, or condensed, e.g. to abenzo[1,3]dioxole or 2,3-dihydrobenzo[1,4]dioxine and/or to a furtherheterocyclic ring. C₅-C₁₀heteroaryl is an aromatic heterocyclic systemwherein one or more carbon atoms are replaced by hetero atoms. Preferredare 5 to 9 membered ring systems containing one, two or three heteroatoms. Examples of C₅-C₁₀aryl or C₅-C₁₀heteroaryl residues as mentionedabove include phenyl, naphthyl, isobenzofuranyl, thienyl, indolyl.

The term “alkyl” represents a straight-chain or branched-chain alkylgroup, preferably represents a straight-chain or branched-chainC₁₋₇alkyl, particularly preferably represents a straight-chain orbranched-chain C₁₋₄alkyl; for example, methyl, ethyl, n- or iso-propyl,n-, iso-, sec- or tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, n-decyl, n-undecyl, n-dodecyl, with particular preference givento methyl, ethyl, n-propyl and iso-propyl.

Each alkyl part of “alkoxy”, “alkoxyalkyl”, “alkoxycarbonyl”,“alkoxycarbonylalkyl” and “halogenalkyl” shall have the same meaning asdescribed in the above-mentioned definition of “alkyl”. Alkoxy isespecially C₁-C₄alkoxy, in particular methoxy, ethoxy or n-propoxy.

“Hetero atoms” are atoms other than Carbon and Hydrogen, preferablyNitrogen (N), Oxygen (O) or Sulfur (S).

“Halogen” represents Fluoro, Chloro, Bromo or Iodo, preferablyrepresents Fluoro, Chloro or Bromo and particularly preferablyrepresents Chloro.

On account of the asymmetrical carbon atom(s) present in the compoundsof formula I and their salts, the compounds may exist in opticallyactive form or in form of mixtures of optical isomers, e.g. in form ofracemic mixtures. All optical isomers and their mixtures including theracemic mixtures are part of the present invention.

In view of the close relationship between the novel compounds in freeform and those in the form of their salts, including those salts thatcan be used as intermediates, for example in the purification oridentification of the novel compounds, any reference to the freecompounds hereinbefore and hereinafter is to be understood as referringalso to the corresponding salts, as appropriate and expedient.

Where the plural form is used for compounds, salts, and the like, thisis taken to mean also a single compound, salt, or the like.

Preferred substituents, preferred ranges of numerical values orpreferred ranges of the radicals present in the formula (I) and thecorresponding intermediate compounds are defined below. Thesesubstituents, preferred ranges of numerical values or preferred rangesare preferred independently, collectively or in any combination orsub-combination:

-   X preferably represents CH₂.-   A and B preferably form together with the carbon atom to which they    are attached a C₃-C₇cycloalkyl group.-   A and B particularly preferably form together with the carbon atom    to which they are attached a cyclopropyl group.-   A and B preferably represent, independent from each other, hydrogen    or C₁-C₄alkyl under the proviso that not both A and B can represent    hydrogen at the same time.-   A and B particularly preferably represent, independent from each    other, hydrogen or C₁-C₂alkyl under the proviso that not both A and    B can represent hydrogen at the same time.-   A very particularly preferably represents hydrogen and B represents    methyl.-   Y preferably represents one of the following groups:

-   Y particularly preferably represents the following group:

-   R preferably represents C₅-C₁₀aryl, which is unsubstituted or    substituted by one or more substituents, the substituents selected    from the group consisting of halogen; NO₂; CN; C₁-C₄alkoxy which is    unsubstituted or substituted by halogen; C₁-C₄alkyl which is    unsubstituted or substituted by halogen, C₁-C₄alkylC(O)NH,    C₁-C₄alkylsulfonyl.-   R preferably represents hetero-C₅-C₁₀aryl, which is unsubstituted or    substituted by one or more substituents, the substituents selected    from the group consisting of halogen; C₁-C₂alkoxy; CN or C₁-C₂alkyl    which is unsubstituted or substituted by halogen.-   R preferably represents N(R¹)(R⁵) or N(R²)(CHR³R⁴).-   R particularly preferably represents phenyl or substituted phenyl,    the substituents being selected from the group consisting of    chlorine, fluorine, methyl, ethyl, methoxy, trifluoromethyl,    trifluoromethoxy, cyano, nitro, acetamide, methylsulfonyl.-   R particularly preferably represents unsubstituted or substituted    hetero-C₅-C₁₀aryl, the hetero-C₅-C₁₀aryl selected from the group    consisting of imidazolyl, triazolyl, tetrazolyl, furanyl,    thiophenyl, benzo[b]thiophenyl, oxazolyl, isocazolyl, thiazolyl,    isothiazolyl, 1-isobenzofuranyl, benzo[1,3]-dioxolyl,    2,3-dihydrobenzo[1,4]-dioxinyl, benzo[1,2,5]oxadiazolyl,    benzo[1,2,5]thiadiazolyl, chinolinyl, isochinolinyl; the    substituents selected from the group consisting of chlorine;    fluorine, methyl, ethyl, methoxy, trifluoromethyl, trifluoromethoxy,    cyano, nitro, acetamide.-   R very particularly represents 5-indolyl.-   R very particularly represents 5-methyl-2-thiophenyl.-   R¹, R² and R³ preferably represent, independently H, C₁-C₄alkyl, or    CF₃.-   R⁴ preferably represents C₅-C₁₀aryl or hetero-C₅-C₁₀aryl, which is    unsubstituted or substituted by one or more substituents the    substituents selected from the group consisting of halogen,    C₁-C₄alkoxy, CN or C₁-C₂alkyl which is unsubstituted or substituted    by halogen.-   R⁵ preferably represents C₅-C₁₀aryl or hetero-C₅-C₁₀aryl, which is    unsubstituted or substituted by one or more substituents the    substituents selected from the group consisting of halogen,    C₁-C₄alkoxy, CN or C₁-C₂alkyl which is unsubstituted or substituted    by halogen.

Preferred are compounds of formula (I) wherein A represents hydrogen, Brepresents methyl and B is in the trans-Position to the oxygen.

Further, preferred are compounds of formula (I) wherein the startingmaterial of formula (III) is the (−) alcohol and the compound of formula(II) is a pyridazine or pyrimidine derivative.

Further, preferred are compounds of formula (I) wherein the startingmaterial of formula (III) is the (+) alcohol and the compound of formula(II) is a pyridine derivative.

In particular compounds of formula I are preferred, wherein

X is CH₂ or a single bond,Y is a group of formula

A and B, independently of each other, represent hydrogen or C₁-C₇alkylunder the proviso that not both A and B can represent hydrogen at thesame time, or

A and B together with the carbon atom to which they are attached form aC₃-C₇cycloalkyl group,R is C₅-C₁₀aryl, which is unsubstituted or substituted by one or moresubstituents selected from halogen, NO₂, CN, C₁-C₄alkoxy which isunsubstituted or substituted by halogen, or C₁-C₁₀alkyl which isunsubstituted or substituted by halogen; hetero-C₅-C₁₀aryl, which isunsubstituted or substituted by one or more substituents selected fromhalogen, C₁-C₄alkoxy, CN or C₁-C₂alkyl which is unsubstituted orsubstituted by halogen; N(R¹)(R⁴) or N(R²)(CHR³R⁴);each of R¹, R² and R³ is independently H, C₁-C₄alkyl, or CF₃; andR⁴ is C₅-C₁₀aryl, which is unsubstituted or substituted by one or moresubstituents selected from halogen, C₁-C₄alkoxy, CN or C₁-C₂alkyl whichis unsubstituted or substituted by halogen; or hetero-C₅-C₁₀aryl, whichis unsubstituted or substituted by one or more substituents selectedfrom halogen, C₁-C₄alkoxy, CN or C₁-C₂alkyl which is unsubstituted orsubstituted by halogen.

Further, a preferred embodiment of the present invention relates tocompounds of formula I, wherein

X is CH₂ or a single bond,Y is a group of formula

A and B, independently of each other, represent hydrogen or C₁-C₄alkylunder the proviso that not both A and B can represent hydrogen at thesame time, orA and B together with the carbon atom to which they are attached form aC₃-C₄cycloalkyl group,and R is phenyl, which is unsubstituted or substituted by one or moresubstituents selected from halogen, NO₂, C₁-C₄alkoxy which isunsubstituted or substituted by halogen, or C₁-C₄alkyl which isunsubstituted or substituted by halogen.

Particularly preferred compounds of the invention are the compounds ofthe Examples.

In a further aspect, the present invention provides a process for theproduction of a compound of formula I, which process comprises the stepof reacting a compound of formula II

Z—Y—R  (II)

wherein Y and R are as defined above for a compound of formula I and Zis a leaving group, e.g. F, Cl, Br, I or OSO₂CF₃, with a compound offormula III

wherein A, B, X and Y have the meanings as defined for a compound offormula I, and recovering the so obtained compound of formula I in freebase or acid addition salt form.

The reaction may be carried out in accordance with standard procedures,for example as illustrated in the Examples.

Compounds of formula II are known or may be prepared from correspondingknown compounds, e.g. as described in the Examples, e.g. in analogy toCoates W J, McKillop A (1992) Synthesis 334-342. The compounds offormula III are known (Vorob'eva, V. Ya.; Bondarenko, V. A.; Mikhlina,E. E.; Turchin, K. F.; Linberg, L. F.; Yakhontov, L. N. Reaction of2-methylene-3-oxoquinuclidine with nucleophilic reagents. KhimiyaGeterotsiklicheskikh Soedinenii (1977), (10), 1370-6).

Alternatively, the compounds of formula I′

whereinA, B, X and R are as defined above for a compound of formula I andY′ represents one of the following groups

can be produced by a process comprising the step of reacting a compoundof formula IV

whereinA, B and X are as defined above for a compound of formula I andY′ is as defined above for a compound of formula I′,Z′ representswith a compound of formula V

whereinR is as defined above for a compound of formula IB represents a Boron atom,and recovering the so obtained compound of formula I′ in free base oracid addition salt form.

Compounds of formula IV are known or may be prepared from correspondingknown compounds, e.g. by reacting compounds of formula III withcompounds of formula II′;

Z—Y′—OH  (II′);

whereinY′ represents one of the following groups:

Z is as defined above.

Compounds of formula V (e.g. unsubstituted or substituted phenylboronicacids) are known or may be prepared from corresponding known compounds.

The following considerations apply to the individual reaction stepsdescribed above:

a) One or more functional groups, for example carboxy, hydroxy, amino,or mercapto, may need to be protected in the starting materials byprotecting groups. The protecting groups employed may already be presentin precursors and should protect the functional groups concerned againstunwanted secondary reactions, such as acylations, etherifications,esterifications, oxidations, solvolysis, and similar reactions. It is acharacteristic of protecting groups that they lend themselves readily,i.e. without undesired secondary reactions, to removal, typically bysolvolysis, reduction, photolysis or also by enzyme activity, forexample under conditions analogous to physiological conditions, and thatthey are not present in the end-products. The specialist knows, or caneasily establish, which protecting groups are suitable with thereactions mentioned hereinabove and hereinafter. The protection of suchfunctional groups by such protecting groups, the protecting groupsthemselves, and their removal reactions are described for example instandard reference works, such as J. F. W. McOmie, “Protective Groups inOrganic Chemistry”, Plenum Press, London and New York 1973, in T. W.Greene, “Protective Groups in Organic Synthesis”, Wiley, New York 1981,in “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer),Academic Press, London and New York 1981, in “Methoden der organischenChemie” (Methods of organic chemistry), Houben Weyl, 4th edition, Volume15/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H.Jescheit, “Aminosauren, Peptide, Proteine” (Amino acids, peptides,proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, andin Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharide andDerivate” (Chemistry of carbohydrates: monosaccharides and derivatives),Georg Thieme Verlag, Stuttgart 1974.b) Acid addition salts may be produced from the free bases in knownmanner, and vice-versa. Alternatively, optically pure starting materialscan be used. Suitable acid addition salts for use in accordance with thepresent invention include for example the hydrochloride.c) Stereoisomeric mixtures, e.g. mixtures of diastereomers, can beseparated into their corresponding isomers in a manner known per se bymeans of suitable separation methods. Diastereomeric mixtures forexample may be separated into their individual diastereomers by means offractionated crystallization, chromatography, solvent distribution, andsimilar procedures. This separation may take place either at the levelof a starting compound or in a compound of formula I itself. Enantiomersmay be separated through the formation of diastereomeric salts, forexample by salt formation with an enantiomer-pure chiral acid, or bymeans of chromatography, for example by HPLC, using chromatographicsubstrates with chiral ligands. Alternatively, optically pure startingmaterials can be used.d) Suitable diluents for carrying out the above-described are especiallyinert organic solvents. These include, in particular, aliphatic,alicyclic or aromatic, optionally halogenated hydrocarbons, such as, forexample, benzine, benzene, toluene, xylene, chlorobenzene,dichlorobenzene, petroleum ether, hexane, cyclohexane, dichloromethane,chloroform, carbon tetrachloride; ethers, such as diethyl ether,diisopropyl ether, dioxane, tetrahydrofuran or ethylene glycol dimethylether or ethylene glycol diethyl ether; ketones, such as acetone,butanone or methyl isobutyl ketone; nitriles, such as acetonitrilepropionitrile or butyronitrile; amides, such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-formanilide, N-methyl-pyrrolidone orhexamethylphosphoric triamide; esters, such as methyl acetate or ethylacetate, sulphoxides, such as dimethyl sulphoxide, alcohols, such asmethanol, ethanol, n- or i-propanol, ethylene glycol monomethyl ether,ethylene glycol monoethyl ether, diethylene glycol monomethyl ether,diethylene glycol monoethyl ether. Further, mixtures of diluents may beemployed. Depending on the starting materials, reaction conditions andauxiliaries, water or diluents containing water may be suitable. It isalso possible to use one a starting material as diluent simultaneously.e) Reaction temperatures can be varied within a relatively wide range.In general, the processes are carried out at temperatures between 0° C.and 150° C., preferably between 10° C. and 120° C. Deprotonationreactions can be varied within a relatively wide range. In general, theprocesses are carried out at temperatures between −150° C. and +50° C.,preferably between −75° C. and 0° C.f) The reactions are generally carried out under atmospheric pressure.However, it is also possible to carry out the processes according to theinvention under elevated or reduced pressure—in general between 0.1 barand 10 bar.g) Starting materials are generally employed in approximately equimolaramounts. However, it is also possible to use a relatively large excessof one of the components. The reaction is generally carried out in asuitable diluent in the presence of a reaction auxiliary, and thereaction mixture is generally stirred at the required temperature for anumber of hours.h) Working up the reaction mixtures according to the above processes andpurification of the compounds thus obtained may be carried out inaccordance to known procedures (cf. the Preparation Examples).

Compounds of formula (I) and their pharmaceutically acceptable acidaddition salts, hereinafter referred to as agents of the invention,exhibit valuable pharmacological properties and are therefore useful aspharmaceuticals.

The compounds of the invention and their pharmaceutically acceptableacid addition salts, hereinafter referred to as compounds of theinvention, exhibit valuable pharmacological properties when tested invitro and in animals, and are therefore useful as pharmaceuticals.

Thus, the compounds of the invention are found to be cholinergic ligandsof the nAChR. In addition preferred compounds of the invention showselective α7-nAChR activity. The compounds of the present invention mayin particular be found to be agonists, partial agonists; antagonists orallosteric modulators of the receptor.

Due to their pharmacological profiles, compounds of the invention areanticipated to be useful for the treatment of diseases or conditions asdiverse as CNS related diseases; PNS related diseases, diseases relatedto inflammation, pain and withdrawal symptoms caused by an abuse ofchemical substances, diseases or disorders related to the CNS includegeneral anxiety disorders, cognitive disorders, learning and memorydeficits and dysfunctions, Alzheimer's disease, ADHD, Parkinson'sdisease, Huntington's disease, ALS, prionic neuro-degenerative disorderssuch as Creutzfeld-Jacob disease and kuru disease, Gilles de laTourette's syndrome, psychosis, depression and depressive disorders,mania, manic de-pression, schizophrenia, the cognitive deficits inschizophrenia, obsessive compulsive disorders, panic disorders, eatingdisorders, narcolepsy, nociception, AIDS-dementia, senile dementia, mildcognitive dysfunctions related to age, autism, dyslexia, tardivedyskinesia, epilepsy, and convulsive disorders, post-traumatic stressdisorders, transient anoxia, pseudodementia, pre-menstrual syndrome,late luteal phase syndrome, chronic fatigue syndrome and jet lag.Furthermore, compounds of the invention may be useful for the treatmentof endocrine disorders, such as thyrotoxicosis, pheochromocytoma,hypertension and arrhythmias as well as angina pectoris, hyperkinesia,premature ejaculation and erectile difficulty. Still further, compoundsof the invention may be useful in the treatment of inflammatorydisorders (Wang et al., Nature 2003, 421,384), disorders or conditionsincluding inflammatory skin disorders, Crohn's disease, inflammatorybowel disease, ulcerative colitis and diarrhea. Compounds of theinvention may further be useful for the treatment of withdrawal symptomscaused by termination of the use of addictive substances, like tobacco,nicotine, opioids, benzodiazepines and alcohol. Finally, compounds ofthe invention may be useful for the treatment of pain, e.g. caused bymigraine, postoperative pain, phantom limb pain or pain associated withcancer. The pain may comprise inflammatory or neuropathic pain, centralpain, chronic headache, pain related to diabetic neuropathy, to posttherapeutic neuralgia or to peripheral nerve injury.

Furthermore, degenerative ocular disorders which may be treated includeocular diseases which may directly or indirectly involve thedegeneration of retinal cells, including ischemic retinopathies ingeneral, anterior ischemic optic neuropathy, all forms of opticneuritis, age-related macular degeneration (AMD), in its dry forms (dryAMD) and wet forms (wet AMD), diabetic retinopathy, cystoid macularedema (CME), retinal detachment, retinitis pigmentosa, Stargardt'sdisease, Best's vitelliform retinal degeneration, Leber's congenitalamaurosis and other hereditary retinal degenerations, pathologic myopia,retinopathy of prematurity, and Leber's hereditary optic neuropathy,

In another aspect, the compounds of the invention are used as diagnosticagents and/or PET ligands, e.g. for the identification and localizationof nicotine receptors in various tissues. Properly isotope-labeledagents of the invention exhibit valuable properties as histopathologicallabeling agents, imaging agents and/or biomarkers, hereinafter“markers”, for the selective labeling of the nAChR. More particularlythe agents of the invention are useful as markers for labeling thealpha7 nAChR receptors in vitro or in vivo. In particular, compounds ofthe invention which are properly isotopically labeled are useful as PETmarkers. Such PET markers are labeled with one or more atoms selectedfrom the group consisting of ¹¹C, ¹³N, ¹⁵O, ¹⁸F.

The agents of the invention are therefore useful, for instance, fordetermining the levels of receptor occupancy of a drug acting at thenAChR, or diagnostic purposes for diseases resulting from an imbalanceor dysfunction of nAChR, and for monitoring the effectiveness ofpharmacotherapies of such diseases.

In accordance with the above, the present invention provides an agent ofthe invention for use as a marker for neuroimaging.

In a further aspect, the present invention provides a composition forlabeling brain and peripheral nervous system structures involving nAChRin vivo and in vitro comprising an agent of the invention.

In still a further aspect, the present invention provides a method forlabeling brain and peripheral nervous system structures involving nAChRin vitro or in vivo, which comprises contacting brain tissue with anagent of the invention.

The method of the invention may comprise a further step aimed atdetermining whether the agent of the invention labeled the targetstructure. Said further step may be effected by observing the targetstructure using positron emission tomography (PET) or single photonemission computed tomography (SPECT), or any device allowing detectionof radioactive radiations.

In particular, the agents of the invention are α7 nicotinicacetylcholine receptor (α7 nAChR) agonists.

In functional assays, the agents of the invention display high affinityat the α7 nAChR as shown in the following tests:

a) A functional assay for affinity at the α7 nAChR is carried out with arat pituitary cell line stably expressing the α7 nAChR. Briefly, GH3cells recombinantly expressing the nAChR α7 were seeded 72 h prior tothe experiment on black 96-well plates and incubated at 37° C. in ahumidified atmosphere (5% CO₂/95% air). On the day of the experimentmedium was removed by flicking the plates and replaced with 100 μlgrowth medium containing of fluorescent calcium sensitive dye, in thepresence of 2.5 mM probenecid (Sigma). The cells were incubated at 37°C. in a humidified atmosphere (5% CO₂/95% air) for 1 h. Plates wereflicked to remove excess of Fluo-4, washed twice with Hepes-bufferedsalt solution (in mM: NaCl 130, KCl 5.4, CaCl₂, MgSO₄ 0.8, NaH₂PO₄ 0.9,glucose 25, Hepes 20, pH 7.4; HBS) and refilled with 100 μl of HBScontaining antagonists when appropriate. The incubation in the presenceof the antagonist lasted between 3 and 5 minutes. Plates were thenplaced into an imaging plate reader and fluorescence signal recorded Inthis assay, compounds of the invention exhibit pEC₅₀ values of about 5to about 9. Partial and potent agonists in this test are preferred.b) To assess the antagonist activity of the compounds of the inventionon the human neuronal nAChR α4β2, a similar functional assay is carriedout using a human epithelial cell line stably expressing the human α4β2subtype (Michelmore et al., Naunyn-Schmiedeberg's Arch. Pharmacol.(2002) 366, 235) In this assay, the preferred compounds of the inventionshow selectivity for the α7 nAChR subtypes.c) To assess the antagonist activity of the compounds of the inventionon the “ganglionic subtype” (α3β4), the muscle type of nicotinicreceptor (α1β1γδ) and the 5-HT₃ receptor, similar functional tests asjust described under a) are carried out with a human epithelial cellline stably expressing the human ganglionic subtype, a cell lineendogenously expressing the human muscle type of nicotinic receptors ora cell line endogenously expressing the murine 5-HT₃ receptor(Michelmore et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (2002) 366,235. Compounds which display little or no activity on the α3β4 nAChR,the muscle subtype of nicotinic receptor as well as the 5-HT₃ receptorare especially preferred.

In the model of mice showing sensory gating deficit (DBA/2-mice)described by S. Leonard et al. in Schizophrenia Bulletin 22, 431-445(1996), the compounds of the invention induce significant sensory gatingat concentrations of about 10 to about 40 μM.

The compounds of the invention may be shown to increase attention in atest of attention for rodents (Robbins, J. Neuropsychiatry Clin.Neurosci. (2001) 13, 326-35), namely the 5-choice serial reaction timetest (5-CSRTT). In this test, the rat must observe a wall containing 5holes. When a light flash appears in one of them, the rat must respondwith a nose-poke into the correct hole within 5 sec. in order to receivea food pellet reward, delivered to a feeder in the opposite wall.

Compounds of the invention may also show learning/memory enhancingeffects in the social recognition test in mice and rats (Ennaceur andDelacour, Behay. Brain Res. (1988) 31, 47-59).

The compounds of the invention are therefore useful for the preventionand treatment (including mitigation and prevention) of variousdisorders, especially those mentioned above. The usefulness of α7 nAChRagonists in neurodegeneration is documented in the literature, e.g. inWang et al., J. Biol. Chem. 275, 5626-5632 (2000).

For the treatment of the above and other disorders, the appropriatedosage of a compound (active ingredient) of the invention will, ofcourse, vary depending upon, for example, the host, the mode ofadministration and the nature and severity of the condition beingtreated as well as the relative potency of the particular agent of theinvention employed. For example, the amount of active agent required maybe determined on the basis of known in vitro and in vivo techniques,determining how long a particular active agent concentration in theblood plasma re-mains at an acceptable level for a therapeutic effect.In general, satisfactory results in animals are indicated to be obtainedat daily dosages of from about 0.01 to about 30.0 mg/kg p.o. In humans,an indicated daily dosage is in the range of from about 0.7 to about1400 mg/day p.o., e.g. from about 50 to 200 mg (70 kg man), convenientlyadministered once or in divided doses up to 4× per day or in sustainedrelease form. Oral dosage forms accordingly suitably comprise from about1.75 or 2.0 to about 700 or 1400 mg of a compound of the inventionadmixed with an appropriate pharmaceutically acceptable diluent orcarrier therefor.

Pharmaceutical compositions contain, for example, from about 0.1% toabout 99.9%, preferably from about 20% to about 60%, of the activeingredient(s).

Examples for compositions comprising a compound of the inventioninclude, for example, a solid dispersion, an aqueous solution, e.g.containing a solubilising agent, a microemulsion and a suspension of,e.g. a salt of a compound of formula I or a free compound of the formulaI in the range of from 0.1 to 1%, e.g. 0.5%. The composition may bebuffered to a pH in the range of, e.g. from 3.5 to 9.5, e.g. to pH 4.5,by a suitable buffer.

The compounds of the invention are also commercially useful as researchchemicals.

For use according to the invention, a compound of the formula I and/or apharmaceutically acceptable salt thereof may be administered as singleactive agent or in combination with one or more other active agents ofthe formula I and/or a pharmaceutically acceptable salt thereof orespecially other active agents commonly employed especially for thetreatment of the disorders mentioned herein or further other disorders,in any customary manner, e.g. orally, for example in the form oftablets, capsules, or as nasal spray, or parenterally, for example inthe form of injection solutions or suspensions. Such other active agentsemployed in such combinations are preferably selected from the groupconsisting of benzodiazepines, selective serotonin reuptake inhibitors(SSRIs), selective serotonin and norepinephrine reuptake inhibitors(SNRIs), conventional antipsychotics, atypical antipsychotics,buspirone, carbamazepine, oxcarbazepine, gabapentin and pregabalin.

An SSRI suitable for the present invention is especially selected fromfluoxetine, fuvoxamine, sertraline, paroxetine, citalopram andescitalopram. An SNRI suitable for the present invention is especiallyselected from venlafaxine and duloxetine. The term “benzodiazepines” asused herein includes, but is not limited to clonazepam, diazepam andlorazepam. The term “conventional antipsychotics” as used hereinincludes, but is not limited to haloperidol, fluphenazine, thiotixeneand flupentixol. The term “atypical antipsychotics” as used hereinrelates to clozaril, risperidone, olanzapine, quetiapine, ziprasidoneand aripiprazol.

Buspirone can be administered in free form or as a salt, e.g. as itshydrochloride, e.g., in the form as marketed, e.g. under the trademarkBuspar™ or Bespar™. It can be prepared and administered, e.g., asdescribed in U.S. Pat. No. 3,717,634. Fluoxetine can be administered,e.g., in the form of its hydrochloride as marketed, e.g. under thetrademark Prozac™. It can be prepared and administered, e.g., asdescribed in CA 2002182. Paroxetine((3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine)can be administered, e.g., in the form as marketed, e.g. under thetrademark Paxil™. It can be prepared and administered, e.g., asdescribed in U.S. Pat. No. 3,912,743. Sertraline can be administered,e.g., in the form as marketed, e.g. under the trademark Zoloft™. It canbe prepared and administered, e.g., as described in U.S. Pat. No.4,536,518. Clonazepam can be administered, e.g., in the form asmarketed, e.g. under the trademark Antelepsin™. Diazepam can beadministered, e.g., in the form as marketed, e.g. under the trademarkDiazepam Desitin™. Lorazepam can be administered, e.g., in the form asmarketed, e.g. under the trademark Tavor™. Citalopram can beadministered in free form or as a salt, e.g. as its hydrobromide, e.g.,in the form as marketed, e.g. under the trademark Cipramil™.Escitalopram can be administered, e.g., in the form as marketed, e.g.under the trademark Cipralex™. It can be prepared and administered,e.g., as described in AU623144. Venlafaxine can be administered, e.g.,in the form as marketed, e.g. under the trademark Trevilor™. Duloxetinecan be administered, e.g., in the form as marketed, e.g. under thetrademark Cymbalta™. It may be prepared and administered, e.g., asdescribed in CA 1302421. Carbamazepine can be administered, e.g., in theform as marketed, e.g. under the trademark Tegretal™ or Tegretol™.Oxcarbazepine can be administered, e.g., in the form as marketed, e.g.under the trademark Trileptal™. Oxcarbazepine is well known from theliterature [see for example Schuetz H. et al., Xenobiotica (GB), 16(8),769-778 (1986)]. Gabapentin can be administered, e.g., in the form asmarketed, e.g. under the trademark Neurontin™. Haloperidol can beadministered, e.g., in the form as marketed, e.g. under the trademarkHaloperidol STADA™. Fluphenazine can be administered, e.g., in the formof its dihydrochloride as marketed, e.g. under the trademark Prolixin™Thiothixene can be administered, e.g., in the form as marketed, e.g.under the trademark Navane™. It can be prepared, e.g., as described inU.S. Pat. No. 3,310,553. Flupentixol can be administered for instance inthe form of its dihydrochloride, e.g., in the form as marketed, e.g.under the trademark Emergil™ or in the form of its decanoate, e.g., inthe form as marketed, e.g. under the trademark Depixol™. It can beprepared, e.g., as described in BP 925,538. Clozaril can beadministered, e.g., in the form as marketed, e.g. under the trademarkLeponex™. It can be prepared, e.g., as described in U.S. Pat. No.3,539,573. Risperidone can be administered, e.g., in the form asmarketed, e.g. under the trademark Risperdal™. Olanzapine can beadministered, e.g., in the form as marketed, e.g. under the trademarkZyprexa™ Quetiapine can be administered, e.g., in the form as marketed,e.g. under the trademark Seroquel™. Ziprasidone can be administered,e.g., in the form as marketed, e.g. under the trademark Geodon™. It canbe prepared, e.g., as described in GB 281,309. Aripiprazole can beadministered, e.g., in the form as marketed, e.g. under the trademarkAbilify™. It can be prepared, e.g., as described in U.S. Pat. No.5,006,528.

The structure of the active ingredients identified by code nos., genericor trade names may be taken from the actual edition of the standardcompendium “The Merck Index” or from databases, e.g. PatentsInternational (e.g. IMS World Publications). The corresponding contentthereof is hereby incorporated by reference. Any person skilled in theart is fully enabled to identify the active ingredients and, based onthese references, likewise enabled to manufacture and test thepharmaceutical indications and properties in standard test models, bothin vitro and in vivo.

In the case of a combination, the pharmaceutical compositions forseparate administration of the combination partners and/or those foradministration in a fixed combination, i.e. a single galenicalcomposition comprising at least two combination partners, according tothe invention can be prepared in a manner known per se and are thosesuitable for enteral, such as oral or rectal, and parenteraladministration to mammals, including man, comprising a therapeuticallyeffective amount of at least one pharmacologically active combinationpartner alone or in combination with one or more pharmaceuticallyacceptable carriers, especially suitable for enteral or parenteralapplication. When the combination partners employed are applied in theform as marketed as single drugs, their dosage and mode ofadministration can take place in accordance with the informationprovided on the packet leaflet of the respective marketed drug in orderto result in the beneficial effect described herein, if not mentionedherein otherwise.

Pharmaceutical preparations for the combination therapy for enteral orparenteral administration are, for example, those in unit dosage forms,such as sugar-coated tablets, tablets, capsules or suppositories, orfurthermore ampoules. If not indicated otherwise, these are prepared ina manner known per se, for example by means of conventional mixing,granu-lating, sugar-coating, dissolving or lyophilizing processes. Itwill be appreciated that the unit content of a combination partnercontained in an individual dose of each dosage form need not in itselfconstitute an effective amount since the necessary effective amount caninstead with a single dosage unit also be reached by administration of atwo or more dosage units.

In particular, a therapeutically effective amount of each of thecombination partners may be administered simultaneously or sequentiallyand in any order, and the components may be administered separately(e.g. sequentially after fixed or variable periods of time), or as afixed combination. For example, the method of treatment (includingmitigation) of a disorder according to the invention may comprise (i)administration of the combination partner (a) (a compound of the presentinvention) in free or pharmaceutically acceptable salt form and (ii)administration of a combination partner (b) (e.g. a different compoundof the present invention or an active ingredient of a different formula)in free or pharmaceutically acceptable salt form, simultaneously orsequentially in any order, in jointly therapeutically effective amounts,preferably in synergistically effective amounts, e.g. in daily dosagescorresponding to the amounts described herein. The individualcombination partners can be administered separately at different timesduring the course of therapy or concurrently in divided or singlecombination forms. Furthermore, the term “administering” alsoencompasses the use of a pro-drug of a combination partner that convertin vivo to the combination partner as such. The instant invention istherefore to be understood as embracing all such regimes of simultaneousand/or alternating treatment and the term “administering” is to beinterpreted accordingly.

The effective dosage of the combination partners employed may vary, forexample depending on the particular compound or pharmaceuticalcomposition employed, the mode of ad-ministration, the disorder beingtreated, and/or the severity of the disorder being treated. Thus, thedosage regimen is selected in accordance with a variety of factorsincluding the route of administration, metabolism by and the renal andhepatic function of the patient. A physician, clinician or veterinarianof ordinary skill can readily determine and prescribe the effectiveamount of the single active ingredients required to prevent, mitigate,counter or arrest the disorder. Optimal precision in achievingconcentration of the active ingredients within the range that yieldsefficacy without toxicity requires a regimen based on the kinetics ofthe active ingredients' availability to target sites.

In accordance with the foregoing, the present invention also provides:

(1) A compound of the formula I, and/or a salt thereof, for use in thediagnostic or therapeutic treatment of a mammal, especially a human;especially for use as an alpha-7 receptor agonist, for example for usein the treatment (including mitigation) of any one or more disorders,especially of any one or more of the particular disorders set forthhereinbefore and hereinafter.(2) A pharmaceutical composition comprising a compound of the formula I,and/or a pharmaceutically acceptable salt thereof, as active ingredienttogether with a pharmaceutically accept-able diluent or carrier.(2′) A pharmaceutical composition for the treatment or prevention of adisorder in the treatment of which alpha-7 receptor activation plays arole or is involved and/or in which alpha-7 receptor activity isinvolved, especially any one or more of the disorders mentionedhereinbefore or hereinafter, comprising a compound of the formula I,and/or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable diluent or carrier.(3) A method for the treatment of a disorder, especially any one or moreof the particular disorders set forth hereinbefore, in a subject in needof such treatment, comprising administering a pharmaceutically effectiveamount of a compound of the formula I, or a pharmaceutically acceptablesalt thereof.(3′) A method for treating or preventing a disorder in the treatment ofwhich alpha-7 receptor activation plays a role or is involved and/or inwhich alpha-7 receptor activity is involved, comprising administering toa mammal in need thereof a therapeutically effective amount of acompound of the formula I, and/or a pharmaceutically acceptable saltthereof.(4) The use of a compound of the formula I, and/or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament for thetreatment or prevention of a disease or condition in the treatment ofwhich alpha-7 receptor activation plays a role or is involved and/or inwhich alpha-7 receptor activity is involved, especially one or more ofthe disorders mentioned above.(5) A method as defined above comprising co-administration, e.g.concomitantly or in sequence, of a therapeutically effective amount ofan alpha-7 agonist of the formula I, and/or a pharmaceuticallyacceptable salt thereof, and a second pharmaceutically active compoundand/or a pharmaceutically acceptable salt thereof, said secondpharmaceutically active compound and/or salt thereof being especiallyfor use in the treatment of any one or more of the disorders set forthhereinbefore or hereinafter.(6) A combination comprising a therapeutically effective amount of analpha-7 agonist of the formula I, and/or a pharmaceutically acceptablesalt thereof, and a second pharmaceutically active compound and/or apharmaceutically acceptable salt thereof, said second pharmaceuticallyactive compound being especially for use or of use in the treatment ofany one or more of the particular disorders set forth hereinbefore.(7) A product obtained according to the above described process,characterized in that (+)-trans-2-methyl-1-aza-bicyclo[2.2.2]octan-3-olis used as starting material and Y represents pyrimidinyl orpyridazinyl.(7′) A product obtained according to the above described process,characterized in that (−)-trans-2-methyl-1-aza-bicyclo[2.2.2]octan-3-olis used as starting material and Y represents pyridinyl.

The Examples which follow serve to illustrate the invention withoutlimiting the scope thereof.

The following abbreviations are used:

AcOEt ethyl acetateaq. aqueousDEAD diethylazodicarboxylateDMF dimethylformamideEtOH ethanolFC flash chromatographyHV high vacuum

MeOH MeOH

RP-HPLC reversed-phase high performance liquid chromatographyrt room temperaturerac. racematesoln. solution

Temperatures are measured in degrees Celsius. Unless indicatedotherwise, reactions are carried out at room temperature. The structureof final products, intermediates and starting materials is confirmed bystandard analytical methods, e.g. microanalysis and spectroscopiccharacteristics (e.g. MS, IR, NMR).

EXAMPLE 1 Preparation ofRac.-trans-3-[6-(2-Fluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane

A solution of rac.-trans-2-methyl-1-aza-bicyclo[2.2.2]octan-3-ol (1.3mmol) in DMF (5 ml) is treated with sodium hydride (60% in mineral oil;1.3 mmol). After 1 hr at rt, a solution of3-chloro-6-(2-fluoro-4-methyl-phenyl)-pyridazine (1.5 mmol) in DMF (30ml) is added, and the reaction mixture heated to 50° C. for 16 hrs.After cooling to rt, the DMF solution is quenched with a 10% NaClsolution, extracted with methylene dichloride (2×15 ml), followed bysodium chloride solution (20 ml). The organic layer is dried overanhydrous magnesium sulfate, filtered and evaporated to dryness, and theresidual oil purified by silica gel column chromatography (eluent:CH₂Cl₂:CH₃OH:NH₃; 95:5:0.1) to affordrac.-trans-3-[6-(2-Fluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octaneas a colourless solid. MS (ES⁺): m/e=328.4 (MH⁺).

EXAMPLE 2

The following compounds are prepared in a similar manner using theappropriate starting materials:

Rac.-trans-2-Methyl-3-(6-phenyl-pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=296.4 (MH⁺)

EXAMPLE 3

The following compounds can be prepared according to the proceduredescribed in Example 1 using appropriate starting materials:

3a)(2S,3R)-3-[6-(2-Fluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=328.4 (MH⁺)3b)(2R,3S)-3-[6-(2-Fluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=328.4 (MH⁺)3c)(2RS,3RS)-3-[6-(2-Fluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=328.4 (MH⁺)3d)(2SR,3RS)-2-Methyl-3-(6-phenyl-pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=296.4 (MH⁺)3e)(2SR,3RS)-2-Methyl-3-[6-(5-methyl-thiophen-2-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=316 (MH⁺); m.p. 148-150° C.,3f)(2S,3R)-2-Methyl-3-[6-(5-methyl-thiophen-2-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane3g)(2R,3S)-2-Methyl-3-[6-(5-methyl-thiophen-2-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane3h)(2SR,3RS)-3-[5-(1H-Indol-5-yl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=334.4 (MH⁺)3i)(+)-3-[5-(1H-Indol-5-yl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=334.4 (MH⁺), [α]_(D)(25)=+210 (c=1, MeOH)3j)(−)-3-[5-(1H-Indol-5-yl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=334.4 (MH⁺), [α]_(D)(25)=−150 (c=1, MeOH)3k) (2SR,3RS)-3-[6-(1H-Indol-5-yl)-pyridazin-3-yloxy]-2-methyl-1-aza-blcyclo[2.2.2]octane,MS (ES⁺): m/e=335 (MH⁺), m.p. 210-213° C., Chiral chromatography:[column: Chiralpak AD, 250-4.6 mm, 10 μm; Eluent: hexane/EtOH 60:40+0.1%TFA; Flow: 1.0 ml/min.; Detector: UV 254 nm], peak 1: 5.533 min., peak2: 9.258 min3l)(2S,3R)-3-[6-(1H-Indol-5-yl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane3m)(2R,3S)-3-[6-(1H-Indol-5-yl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane3n)(2SR,3RS)-3-[5-(1H-Indol-5-yl)-pyrimidin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=335 (MH⁺), m.p.: 219-222° C.3o)(2S,3R)-3-[5-(1H-Indol-5-yl)-pyrimidin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=335 (MH⁺)3p)(2R,3S)-3-[5-(1H-Indol-5-yl)-pyrimidin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane3q)(2SR,3RS)-3-[6-(2,3-Dimethyl-1H-indol-5-yl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=363 (MH⁺)3r)(2SR,3RS)-3-[5-(1H-Indol-5-yl)-pyrimidin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=335.4 (MH⁺)3s)(2SR,3RS)-3-[6-(2,5-Difluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-azabicyclo[2.2.2]octane,MS (ES⁺): m/e=346 (MH⁺)3t)(2SR,3RS)-2-Methyl-3-(6-p-tolyl-pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=310 (MH⁺)3u)(2SR,3RS)-2-Methyl-3-(6-m-tolyl-pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=310 (MH⁺)3v)(2SR,3RS)-2-Methyl-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=309 (MH⁺)3w)(2SR,3RS)-2-Methyl-3-[6-(3-nitro-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=341 (MH⁺)3x)(2SR,3RS)-N-{3-[6-(2-Methyl-1-aza-bicyclo[2.2.2]oct-3-yloxy)-pyridazin-3-yl]-phenyl}acetamide,MS (ES⁺): m/e=353 (MH⁺)3y)(2SR,3RS)-3-[6-(5-Ethyl-2-fluoro-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=342 (MH⁺)3z)(2SR,3RS)-3-(6-Benzo[1,3]dioxol-5-yl-pyridazin-3-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=340 (MH⁺)3aa)(2SR,3RS)-3-[6-(3-Methoxy-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=326 (MH⁺)3ab)(2SR,3RS)-3-[6-(2-Chloro-4-methyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=344 (MH⁺)3ac)(2SR,3RS)-N-{4-[6-(2-Methyl-1-aza-bicyclo[2.2.2]oct-3-yloxy)-pyridazin-3-yl]-phenyl}-acetamide,MS (ES⁺): m/e=353 (MH⁺)3ad)(2SR,3RS)-2-Methyl-3-[6-(1-methyl-1H-indol-5-yl)-pyridazin-3-yloxy]-1-aza-bicycio[2.2.2]octane,MS (ES⁺): m/e=349 (MH⁺)3ae)(2SR,3RS)-3-[6-(2-Fluoro-5-methoxy-4-methyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=358 (MH⁺)3af)(2SR,3RS)-3-[5-(3,5-Dimethyl-phenyl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=323.2 (MH⁺)3ag)(2SR,3RS)-3-[5-(3,4-Difluoro-phenyl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=331.1 (MH⁺)3ah)(2SR,3RS)-3-[6-(3,4-Dimethyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=324 (MH⁺)3ai)(2SR,3RS)-3-[6-(2-Fluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=328.4 (MH⁺)3aj)(2SR,3RS)-3-[6-(4-Fluoro-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=314 (MH⁺)3ak)(2SR,3RS)-2-Methyl-3-[6-(3-trifluoromethoxy-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=380 (MH⁺)2al)(2SR,3RS)-3-[6-(4-Ethyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=324 (MH⁺)3am)(2SR,3RS)-3-[6-(3,4-Dimethoxy-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=356 (MH⁺)3an)(2SR,3RS)-2-Methyl-3-(5-phenyl-pyridin-2-yloxy)-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=295.5 (MH⁺)3ao)(2SR,3RS)-3-[6-(3-Fluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=328 (MH⁺)3ap)(2SR,3RS)-(2RS,3RS)-2-Methyl-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=309 (MH⁺)3aq)(2SR,3RS)-3-[6-(2,5-Dimethoxy-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=356 (MH⁺)3ar)(2SR,3RS)-2-Methyl-3-(5-phenyl-[1,3,4]thiadiazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=302 (MH⁺)3 as)(2SR,3RS)-3-[6-(3-Chloro-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=330 (MH⁺)3 at)(2SR,3RS)-3-[5-(2-Fluoro-4-methyl-phenyl)-pyrimidin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺); m/e=328 (MH⁺)3au)(2RS,3RS)-3-[6-(4-Ethyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺); m/e=324 (MH⁺)3av)(2RS,3RS)-3-[6-(2,5-Difluoro-4-methyl-phenyl)-Pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=346 (MH⁺)3aw)(2SR,3RS)-2-Methyl-3-[6-(3-trifluoromethyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=364 (MH⁺)3ax)(2RS,3RS)-2-Methyl-3-(6-p-tolyl-pyridazin-3-yloxy)-1,aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=310 (MH⁺)3ay)(2SR,3RS)-2-Methyl-3-(5-m-tolyl-pyridin-2-yloxy)-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=309.1 (MH⁺)3az)(2SR,3RS)-3-(5-Furan-3-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=285.1 (MH⁺)3ba)(2SR,3RS)-3-(5-Benzo[1,3]dioxol-5-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=339.1 (MH⁺)3bb)(2SR,3RS)-2-Methyl-3-(5-p-tolyl-pyridin-2-yloxy)-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=309.2 (MH⁺)3bc)(2SR,3RS)-3-[5-(1H-Indol-6-yl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=334.2 (MH⁺)3bd)(2SR,3RS)-3-[6-(6-Methoxy-pyridin-3-yl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=327 (MH⁺)3be)(2SR,3RS)-2-Methyl-3-[6-(2-methyl-benzothiazol-5-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=367.4 (MH⁺)3bg)(2SR,3RS)-3-[6-(3,4-Dichloro-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=364 (MH⁺)3bh)(2SR,3RS)-3-[5-(2-Fluoro-phenyl)-pyrimidin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=314 (MH⁺)3bi)(2RS,3RS)-2-Methyl-3-(5-phenyl-[1,3,4]thiadiazol-2-yloxy)-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=302 (MH⁺)3bj)(2SR,3RS)-2-Methyl-3-[5-(1-methyl-1H-indol-5-yl)-pyridin-2-yloxy]-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=348.2 (MH⁺)3bk)(2SR,3RS)-3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=313.1 (MH⁺)3bl)(2SR,3RS)-3-[6-(3-Chloro-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=330 (MH⁺)3bm)(2SR,3RS)-2-Methyl-3-(5-phenyl-pyrimidin-2-yloxy)-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=296 (MH⁺)3bn)(2SR,3RS)-2-Methyl-3-(5-p-tolyl-pyrimidin-2-yloxy)-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=310 (MH⁺)3bo)(2RS,3RS)-3-[6-(5-Ethyl-2-fluoro-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=342 (MH⁺)3 bp)(2RS,3RS)-3-[6-(2-Fluoro-5-methoxy-4-methyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=358 (MH⁺)3bq)(2SR,3RS)-3-[5-(2,3-Dimethyl-1H-indol-6-yl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=362.1 (MH⁺)3br)(2RS,3RS)-3-[6-(3-Fluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=328 (MH⁺)3bs)(2SR,3RS)-3-[6-(2,3-Difluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-azabicyclo[2.2.2]octane, MS (ES⁺): m/e=346 (MH⁺)3bt)(2SR,3RS)-3-[5-(4-Methoxy-phenyl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=325.2 (MH⁺)3bu)(2SR,3RS)-3-[5-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=375.4 (MH⁺)3by)(2RS,3RS)-3-[6-(3,4-Dichloro-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=364 (MH⁺)3bw)(2SR,3RS)-3-(5-Biphenyl-4-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=371.1 (MH⁺)3bx)(2SR,3RS)-2-Methyl-3-[6-(3-trifluoromethyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=364 (MH⁺)3by)(2SR,3RS)-3-[5-(2,5-Difluoro-4-methyl-phenyl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=345.2 (MH⁺)3bz)(2SR,3RS)-3-(5-Benzo[1,3]dioxol-5-ylethynyl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=363.9 (MH⁺)3ca)(2SR,3RS)-5-[6-(2-Methyl-1-aza-bicyclo[2.2.2]oct-3-yloxy)-pyridin-3-yl]-quinoline,MS (ES⁺): m/e=346.4 (MH⁺)3cb)(2RS,3RS)-3-[6-(2,3-Difluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=346 (MH⁺)3 cc)(2SR,3RS)-3-[5-(2-Fluoro-4-methyl-phenyl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=327.3 (MH⁺)3cd)(2RS,3RS)-2-Methyl-3-(6-phenyl-pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=296.4 (MH⁺)3ce)(2RS,3RS)-3-[6-(3,4-Dimethyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=324 (MH⁺)3cf)(2RS,3RS)-2-Methyl-3-(6-m-tolyl-pyridazin-3-yloxy)-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=310 (MH⁺)3cg)(2SR,3RS)-3-[6-(4-Methanesulfonyl-phenyl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=374 (MH⁺)3ch)(2SR,3RS)-3-[6-(2-Methyl-1-aza-bicyclo[2.2.2]oct-3-yloxy)-pyridin-3-ylethynyl]-quinoline,MS (ES⁺): m/e=370.0 (MH⁺)3ci)(2SR,3RS)-(2RS,3RS)-2-Methyl-3-[6-(3-trifluoromethoxy-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=380 (MH⁺)3cj)(2SR,3RS)-3-[5-(2,3-Dihydro-benzofuran-5-yl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane,MS (ES⁺): m/e=337.1 (MH⁺)3ck)(2SR,3RS)-3-(5-Iodo-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octaneMS (ES⁺): m/e=345.1 (MH⁺)3cl)(2SR,3RS)-3-(5-Iodo-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane3 cm)(2SR,3RS)-3-(5-Iodo-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane3cn)(2SR,3RS)-3-(5-Benzo[b]thiophen-2-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane3co)(2SR,3RS)-3-(5-Benzo[b]thiophen-3-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane3 cp)(2SR,3RS)-3-(5-Dibenzothiophen-4-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane3cq)(2SR,3RS)-3-(5-Dibenzofuran-4-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane3cr)(2SR,3RS)-2-Methyl-3-[5-(1-phenyl-1H-indol-5-yl)-pyridin-2-yloxy]-1-aza-bicyclo[2.2.2]octane3cs)(2SR,3RS)-3-{5-[1-(4-Methoxy-phenyl)-1H-indol-5-yl]-pyridin-2-yloxy}-2-methyl-1-aza-bicyclo[2.2.2]octane3ct)(2SR,3RS)-3-[5-(1H-Indol-7-yl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane3cu)(2SR,3RS)-3-[5-(1H-Indol-4-yl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane3cv)(2SR,3RS)-3-[5-(1H-Indol-3-yl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane3cw)(2SR,3RS)-3-[5-(1-Benzenesulfonyl-1H-indol-3-yl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane3cx)(2SR,3RS)-3-[5-(1-Benzenesulfonyl-1H-indol-2-yl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane3cy)(2SR,3RS)-3-[5-(1H-Indol-2-yl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane3cz)(2SR,3RS)-3-(5-Benzo[b]thiophen-4-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane3da)(2SR,3RS)-3-(5-Benzo[b]thiophen-7-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane3 db)(2SR,3RS)-3-(5-Benzo[b]thiophen-6-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane3dc)(2SR,3RS)-3-(5-Benzo[b]thiophen-5-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane3dd)(2SR,3RS)-3-(5-Benzofuran-5-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane3de)(2SR,3RS)-3-(5-Benzofuran-6-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane3df)(2SR,3RS)-3-(5-Benzofuran-7-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane3dg)(2SR,3RS)-3-(5-Benzofuran-4-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane3dh)(2SR,3RS)-3-(5-Benzofuran-2-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane3di)(2SR,3RS)-3-(5-Benzofuran-2-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane3dj)(2SR,3RS)-3-(5-Benzo[1,2,5]oxadiazol-5-yl-pyridin-2-yloxy)-2-methyl-1-aza-bicyclo[2.2.2]octane3dk)(2SR,3RS)-2-Methyl-3-[5-(5-methyl-thiophen-2-yl)-Pyridin-2-yloxy]-1-aza-bicyclo[2.2.2]octane3dl)(2SR,3RS)-3-[6-(1H-Indol-5-yl)-pyridin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane3dm)(2SR,3RS)-2-Methyl-3-[6-(1-methyl-1H-indol-5-yl)-pyridin-3-yloxy]-1-aza-bicyclo[2.2.2]octane3dn)(2SR,3RS)-3-[6-(1-Benzyl-1H-indol-5-yl)-pyridin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane3do)(2SR,3RS)-2-Methyl-3-[5-(5-methyl-thiophen-2-yl)-Pyrimidin-2-yloxy]-1-aza-bicyclo[2.2.2]octane

EXAMPLE 4 Soft Capsules

5000 soft gelatin capsules, each comprising as active ingredient 0.05 gof one of the compounds of formula I mentioned in the precedingExamples, are prepared as follows:

Composition

Active ingredient 250 g Lauroglycol 2 litres

Preparation process: The pulverized active ingredient is suspended inLauroglykol® (propylene glycol laurate, Gattefossé S. A., Saint Priest,France) and ground in a wet pulverizer to produce a particle size ofabout 1 to 3 μm. 0.419 g portions of the mixture are then introducedinto soft gelatin capsules using a capsule-filling machine.

1-15. (canceled)
 16. A compound of formula I

wherein A represents hydrogen, B represents methyl and B is in thetrans-position to the oxygen; X represents CH₂; Y represents a group offormula

wherein the left bond is attached to the oxygen and the right bond isattached to the R group; R represents 5-indolyl; in free base or acidaddition salt form.
 17. A compound of formula I according to claim 16,wherein Y is a group of formula


18. A compound of formula I according to claim 16, wherein Y is


19. A compound of formula I according to claim 16 selected from(2SR,3RS)-3-[5-(1H-Indol-5-yl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;(+)-3-[5-(1H-Indol-5-yl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;(−)-3-[5-(1H-Indol-5-yl)-pyridin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;(2SR,3RS)-3-[6-(1H-Indol-5-yl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;(2S,3R)-3-[6-(1H-Indol-5-yl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;(2R,3S)-3-[6-(1H-Indol-5-yl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;(2SR,3RS)-3-[5-(1H-Indol-5-yl)-pyrimidin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;(2S,3R)-3-[5-(1H-Indol-5-yl)-pyrimidin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;(2R,3S)-3-[5-(1H-Indol-5-yl)-pyrimidin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;and(2SR,3RS)-3-[6-(1H-Indol-5-yl)-pyridin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane.20. A compound of formula I according to claim 16, wherein said compoundis(2SR,3RS)-3-[6-(1H-Indol-5-yl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane.21. A compound of formula I according to claim 16, wherein said compoundis(2S,3R)-3-[6-(1H-Indol-5-yl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane.22. A compound of formula I according to claim 16, wherein said compoundis(2R,3S)-3-[6-(1H-Indol-5-yl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane.23. A process for the preparation of a compound of formula I as definedin claim 16, or a salt thereof, which comprises the step of reacting acompound of formula IIZ—Y—R  (II) wherein Y and R are as defined in claim 16 and Z is aleaving group with a compound of formula III

and recovering the so obtained compound of formula I in free base oracid addition salt form.
 24. A pharmaceutical composition comprising acompound of claim 16 in free base or pharmaceutically acceptable acidaddition salt form, in association with a pharmaceutical carrier ordiluent.
 25. A pharmaceutical composition comprising a compound of claim17 in free base or pharmaceutically acceptable acid addition salt form,in association with a pharmaceutical carrier or diluent.
 26. Apharmaceutical composition comprising a compound of claim 18 in freebase or pharmaceutically acceptable acid addition salt form, inassociation with a pharmaceutical carrier or diluent.